PHARMACOLOGICAL EFFICACY OF ALOE VERA IN WOUND HEALING: A NARRATIVE REVIEW

ABSTRACT


PHYTOCHEMISTRY
Aloe vera 'aloe vera' is a xerophytic and succulent species native to Africa; 75 active principles have been found in the plant, and it presents phenolic compounds, mainly chromones and anthraquinones, located in the inner layer of the epidermal cells; the gelatinous and colorless parenchyma is mainly constituted by water, mucilages, acids and organic salts, enzymes, saponins, (7) tannins, traces of alkaloids and vitamins .
Having a high water content is one of the main characteristics of the aloe plant; likewise, the gel is 99% water.In addition, A. vera has many compounds that possess biological activity.It was found that the main compounds of the plant were invariable with aloeresin The bibliographic databases used were the VHL regional portal and PubMed.The search was carried out in June 2021.A secondary search was also performed by reviewing the bibliographic references of the papers that were nally included.The words used for the search and subsequent selection of articles were in the case of the VHL Regional Portal: (aloe vera) AND (wound healing), and in the case of PubMed: ("aloe vera"[All Fields]) AND ("wound healing"[All Fields]).Within the inclusion criteria, articles that included any of the following keywords supported by DeCS, "burns, surgical wounds, anal ssure and stula, and breast ssures" were considered as part of the project.Also included were articles that will feature the word "skin scarring."

SEARCH STRATEGIES
Regarding the years, only articles that met the criteria mentioned above and were also in the range of 10 years old  were included in the research.
However, most of the original articles used had a recent age range; an article from the year 1999 was used because its information is still current as it is cited to date by different authors.According to the type of study, preclinical and clinical studies were included.In the exclusion criteria, review articles and those dealing mainly with non-cutaneous avulsions or wound prevention were not considered as part of the review of the efficacy of using Aloe vera.
In addition, by topical or oral administration1 of Aloe gel on a wound, glucomannans, which are important polysaccharides of this plant, and gibberellin interact with broblast growth factor receptors, stimulating (15,16) their activity and cell proliferation in situ .They also promote collagen production above and across the (16,17) wound, accelerating healing .
The bioactive polysaccharides abundantly present in Aloe vera (AVP), favor broblast proliferation and generation of hyaluronic acid and hydroxyproline in broblasts; therefore, they possibly play an important role in the remodeling of the extracellular matrix (ECM) (13,14,18) during wound healing .
In glycosaminoglycans and collagen . (1,4) Acemannan, a β--soluble acetylated polymannose and considered to be the main functional component of regeneration in the deeper layers of the skin .
A, aloesin and aloin (both epimers A and B) occupying between 70% and 97% of the dry weight of the plant, with an approximate ratio of 4: 3: 2. On the other hand, the minor compounds were less evenly distributed .

MECHANISM OF ACTION
Wound healing is a dynamic process that occurs in three phases.The rst phase is in ammation, hyperemia and leukocyte in ltration.The second phase consists of the elimination of dead tissue.The third phase is proliferation consisting of epithelial regeneration and (1) brous tissue formation .
Aloe vera has been used for many years to treat wounds, burns and various skin conditions.On the other hand, it forms part of cosmetic products due to its moisturizing (9,10) and anti-aging properties on the skin .
It has been demonstrated that Aloe vera has a healing property thanks to the different active molecules that it presents; these act on broblasts, macrophages, and the activity of the cells of the epidermis; in addition, they stimulate the formation of the epidermis, the synthesis, the remodeling process of collagen and (12) improve the tensile stress .This property of Aloe vera (1,13,14) is due to mannose-6-phospha , which binds to (2) broblast growth factor and enhances their activity . (1) En adición, mediante la administración tópica u oral .

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Burn care is often expensive so every effort should be made to provide hospital care in the shortest possible (23) time .Herbal products appear to possess efficacy without toxicity and at less cost than synthetics.The goal of current burn treatments is to accelerate healing and prevent wound infection, as poor healing may be a (24) consequence of pathological conditions .
Aloe vera is one of the effective herbs for healing, as it has organic compounds such as amino acids, polysaccharides in its extracts, which are effective as antimicrobial barriers, rapid healing, maintenance of (25) environmental moisture and pain relief .
of the super cial integument until the total destruction of the tissues involved.They are classi ed by degrees, considering three levels: rst degree, second degree (22) and third degree .
Two preclinical studies and two clinical studies were found that evaluated the effects of Aloe vera on burns, where all of them suggested its capacity as a better healing agent in less time, compared to other compounds.A greater capacity of Aloe vera to decrease pain and in ammation, as well as to increase epithelization and decrease the size of the lesion is also mentioned.However, regarding its competence to prevent wound colonization or infections, the results were not signi cant (Table 1).
Finally, the presence of vitamin C in Aloe vera gel can stimulate the production of collagen, aiding in healing.
In Preclinical study with 4 groups: 0.5% Alore vera gel (experimental group) vs. base cream, 1% silver sulfadiazine and no topical treatment (control groups).Histological outcomes were compared with respect to re-epithelialization in burn wounds after 25 days of treatment.
Aloe vera signi cantly increased re-epithelialization in burn wounds compared to the control groups, proving to be more effective in healing burns in rats.
Pharmacological efficacy of Aloe vera.tissue .
Five preclinical studies and three clinical studies were found that evaluated the effect of Aloe vera on surgical wounds including incisions and excisions in animals, and procedures in humans such as hemorrhoidectomy, episiotomy and cesarean section, using Aloe vera in various formulations as treatment: gel, cream and ointment (Table 2).
With regard to preclinical studies, Hosseinimehr et al. (23) treated thermal burns with Aloe vera gel and found a signi cant increase in re-epithelialization compared to standard treatment with silver sulfadiazine.Similar results were reported in the study by Akhoondinasab et

SURGICAL WOUNDS
Surgical wounds are incisions made during a surgical (25) Regarding clinical studies, Shahzad et al. and (26) Muangman et al. evaluated the effect of Aloe vera on second degree burns.In the former, they applied an aloe vera gel that favored epithelialization and pain relief; while in the latter, they applied dressings with an herbal extract containing aloe vera, presenting a greater decrease in healing time, hospital stay and pain, but reaching up to 64% of patients with bacterial colonization in the wound.Therefore, the results regarding the antimicrobial properties of Aloe are somewhat mixed and further studies on this aspect are recommended.The mixed herbal extract showed a signi cantly greater decrease in healing time, length of hospital stays and pain compared to the control group.In addition, in the experimental group only one person presented infection, while in the control group there were no infections.However, no patients reported unfavorable clinical symptoms/signs or side effects in both groups.

Title Year Sample Methods Results
12 2-to 3month-old male Sprague dawley rats with excisional skin lesions Preclinical study with 2 randomly distributed groups: herbal gel with Aloe vera (experimental group) and placebo (control group) to compare outcomes regarding the wound healing process in 14 days of treatment.
Aloe vera showed a higher percentage of healing compared to placebo, while tissue hyperplasia was lower in the control group.On the other hand, the control group presented in ammation and pus until the 5th day of the study, while the experimental group did not show these complications.

adult male
Wistar rats with cutaneous wounds.
Preclinical study with 3 randomly distributed groups: Aloe vera gel at low-25mg/ml and high 50mg/ml doses (experimental groups) and placebo (control group) to compare outcomes regarding wound healing parameters in 10 days of treatment.Preclinical study with three groups: Plantago major/Aloe vera gel 5% (experimental group) vs. placebo and no treatment (control groups) c/24h for 15 days, to compare outcomes with respect to histological parameters of wound healing.
The herbal combination of Plantago major/Aloe vera presented a signi cantly higher rate of healing and had a signi cantly greater capacity to improve wound healing due to broblast proliferation, collagen bundle synthesis and revascularization in skin lesions.They also presented a higher rate of healing.
Preclinical study with four groups: Aloe vera precipitate, supernatant (experimental groups), ethanol and no lesion (control groups) to compare o u tco m e s w i t h re s p e c t to wo u n d h e a l i n g parameters.
Aloe vera accelerated wound healing and precipitate treatment had a signi cantly superior effect to supernatant in promoting wound healing.
12 male Swiss Webster mice with cutaneous incision wounds Randomized clinical trial with two groups: Aloe vera cream 0.5% (experimental group) vs. placebo (control group), at a dose of 3g c/8h until 28 days postoperative, to compare outcomes regarding postoperative pain, pain on defecation and wound healing status.
Aloe vera cream signi cantly reduced pain with defecation at 24 and 48 hours postoperatively compared to placebo.On the other hand, the Aloe vera cream presented a signi cantly greater healing at 2 weeks of treatment compared to placebo; however, no signi cant differences were observed at the end of 4 weeks.

patients who underwent open hemorrhoidect omy
Randomized clinical trial with three groups: Aloe vera ointment and calendula c/8h (experimental groups) vs. routine care (control group) to compare episiotomy wound healing through the redness, edema, ecchymosis, discharge and approximation (REEDA) scale, after 5 days of inpatient treatment.
Both Aloe vera and calendula ointments signi cantly increased the speed of healing of the episiotomy wound.

primiparous women who underwent episiotomy
Randomized clinical trial with two groups: Aloe vera gel (experimental group) and routine care (control group), to compare outcomes regarding wound healing through the REEDA scale at 24 hours and 8 days postoperatively.
The Aloe vera gel presented signi cantly better healing scores in the rst 24 hours postoperatively compared to the control, however there was no signi cant difference between the groups at 8 days postoperatively.90 women aged 18 to 36 years who underwent cesarean section.

Pharmacological efficacy of Aloe vera.
(35) hand, Eghdampour et al. conducted a study where Aloe vera ointment was applied on episiorrhaphy every eight hours for ve days, nding an increase in the speed of wound healing.Finally, in the study by (36) Molazem et al. bandages with Aloe vera gel were applied on the cesarean surgical wound up to eight d a y s p o s t -o p e r a t i v e l y, s h o w i n g s i g n i c a n t improvements in healing and no side effects.

BREAST FISSURES
Nipple ssures are excoriation or ulcer-like lesions that develop on the mother's nipples and generate great (37) pain during breastfeeding .Two clinical studies were found that evaluated the effect of Aloe vera on breast ssures, both investigations showed that Aloe vera is effective in reducing the intensity of pain and damage to the nipple, improving the condition of breast ssures (Table 3).(29) Regarding preclinical studies, research by Khan et al. ,(30) (31) (32) Oryan et al. , Brandão et al. and Kusmardi et al. used Aloe vera in gel form and observed improved healing parameters at the macroscopic (wound healing and contraction) and microscopic (epithelialization, a l i g n m e n t , t i s s u e o r g a n i z a t i o n , b ro b l a s t i c proliferation) levels in rats.On the other hand, Ashkani- Esfahani et al. studied the use of Aloe vera in combination with Plantago major and observed similar results highlighting a faster wound closure rate.
Regarding clinical studies, it was found that Aloe vera increased and helped in the healing process after its application for ve to 28 days, depending on the wound (34) evaluated.In the study by Eshghi et al. an Aloe vera cream was applied to surgical wounds from hemorrhoidectomy three times a day until 28 days postoperatively, nding signi cantly greater healing only after two weeks of treatment.On the other Two clinical studies were found that evaluated the effect of Aloe vera on anal ssures, using rectal ointment preparations based on Aloe vera, which, together with other methods, achieved wound healing in almost all cases (Table 4).
to the anal margin.Most of these occur in the posterior raphe and usually reduce the patient's quality of life.Anal ssures can be acute, if the lesion does not extend for more than six-eight weeks and heals spontaneously (adhering to conservative measures such as hygienicdietary treatment); or chronic, if they exceed this period (40) and have a high resistance to healing .
In the studies reviewed, it was observed that breast ssures can be effectively treated by topically applying (38) 0.5ml of Aloe vera gel alone or by adding three to four (39) drops of one's own breast milk , three times a day after (38,39) each feeding, on the nipples and around the areola . ( With the above treatment, Alamolhoda et al. and (39) Eshgizade et al. concurred in their ndings, nding a signi cant improvement in the intensity of pain and breast ssure.

Anal ssures
Anal ssures are lesions presenting as short lacerations or ulcerations which may extend from the pectineal line 110 nursing mothers with breast ssure Clinical trial with two groups: Aloe vera gel (experimental group) and breast milk (control group) to compare outcomes regarding pain intensity and breast ssure in 14 days of treatment.
The average intensity of pain and nipple damage, as well as nipple discharge, between the two groups showed signi cant differences, nding that Aloe vera can improve breast ssures.

nursing mothers with breast ssure
Uncontrolled randomized clinical trial with three groups: olive oil vs. aloe vera + breast milk vs. breast milk to compare outcomes regarding pain severity and ssure intensity in 7 days of treatment.
Signi cant differences were found between the groups with respect to the severity of pain and breast ssure.In the Aloe vera group, the severity of pain and the severity of the breast ssure were lower, being more effective compared to the olive oil and breast milk groups.

Title Year Sample Methods Results
Pág. 117 anal crypt where the abscess originated with the perianal skin or with the rectum, so that there will be a primary ori ce (the crypt) and a secondary ori ce (cutaneous or mucosal).There are different types of anal stulas and pain is the main symptom, which is intense (44) and disabling .
Two preclinical studies were found that evaluated the effect of Aloe vera on anal stulas, both were performed on male Wistar albino rats subjected to anal stulas and In both studies, topical application of preparations containing Aloe vera gel (preparations with 0.5% Aloe vera powder and others with Aloe aqueous extract, respectively) three times a day, preceded by sitz baths and associated with a dietary regimen rich in ber and the consumption of laxatives by medical indication was performed.
A signi cant decrease in bleeding and healing times was observed in the rst weeks of treatment.In the rst

ANAL FISTULA
The anal stula is the chronic phase of an anal abscess.This is a duct with brous walls that communicate the

Title Year Sample Methods Results
60 patients aged 20 to 70 years with a diagnosis of chronic anal ssure.
Clinical trial with 2 groups: aloe vera cream (experimental group) and placebo (control group) c/8h for 3 weeks or more to compare outcomes regarding chronic pain, bleeding on defecation and wound healing.
Aloe vera signi cantly decreased chronic anal ssure pain, bleeding on defecation, and wound healing compared to the placebo.
60 and 52 patients with acute hemorrhoidal are-up and anal ssure, respectively.
Clinical trial with two groups of an acute hemorrhoidal areup: Aloe vera ointment (experimental group) and proctocaine (control group) c/8h; and three groups of anal ssure: Aloe vera ointment (experimental group) and proctocaine (control group), both c/8h, and polidocanol 1% c/7d (control group).Outcomes were compared with respect to symptoms, healing and adverse effects in 15 days of treatment.
There were no signi cant differences in the resolution of an acute hemorrhoidal are-up between groups, however, Aloe vera presented greater qualitative disappearance of edema while it did not present adverse effects.On the other hand, polidocanol 1% together with Aloe vera presented total healing and no adverse effects.
Pharmacological efficacy of Aloe vera.It was concluded that Aloe vera possesses different bioactive components, such as the polysaccharides Acemannan and Glucomannan, which contain mannose-6-phosphate; also, phytohormones such as gibberellin; vitamin C; among others.It was determined that these act synergistically in the three phases of the healing process, thus giving Aloe vera its therapeutic property in healing.After the analysis of the studies, the pharmacological efficacy of Aloe vera in wound healing was evidenced.In the case of burns and surgical wounds, it was observed that this medicinal plant generally increased epithelization and collagen content and decreased healing time.Similarly, with CONCLUSION from its topical administration.There is a report of a clinical case in which a six year old patient presented urticaria due to direct contact with aloe vera juice placed on his back, developing within a few minutes con uent and intensely pruritic haematous lesions all (47) over the surface .A case was also reported of a 72year-old female patient who presented a three-month history of pruritic erythema on her legs and eyelids, which appeared shortly after applying Aloe vera leaf juice to her legs.Subsequently, she underwent a twoday patch test and tested positive for reactions to Aloe (48) vera gel .
Among the limitations presented during the development of this review were, in the rst place, those related to language.Most of the articles used in this study were found in languages other than Spanish, such as English and Persian.In the latter, the articles only had the abstract available in English, so it was not possible to obtain more data from the article.On the other hand, some difficulty was encountered when searching for more up-to-date studies on the article's subject, since the vast majority of studies were more than 20 years old.
Finally, in the case of preclinical studies in mice, some samples were not as signi cant as in human studies.

ADVERSE REACTIONS AND CONTRAINDICATIONS
Although aloe vera gel has several bene cial properties that help wound healing and reduce in ammation, there are not many references for its adverse effects.In its topical application, the freshly obtained gel is normally used (100%) or in preparations with 10-70% of fresh gel, this could be contraindicated in people with allergies to plants of the liliaceae family, which could occasionally cause dermatitis, photodermatitis, allergic reactions, delay wound healing or in case of aloemodin, which is one of the components of aloe vera, it is capable of inducing skin alterations produced by (46) ultraviolet radiation .
Aloe vera juice is a product that contains a minimum (8) concentration of 50% Aloe vera gel .About this, there are clinical cases that show adverse reactions resulting

Title
Year Sample Methods Results

adult male
Wistar albino rats with anal stula by anal sphincter section.
P r e c l i n i c a l s t u d y w i t h t h r e e g r o u p s : A l o e v e r a extract/carbapolol (experimental group), carbapolol and no treatment (control groups) to compare outcomes regarding the evolution and histopathological analysis of the stulous tract after 30 days of treatment.
Complete closure of the stulous tract was not observed in any group; however, Aloe vera evidenced a signi cantly greater decrease in lumen diameter and vascular lumen diameter compared to the other groups.30 adult male Wistar albino rats with anal stula by anal sphincter section.
Preclinical study with three groups: Aloe vera extract/seton (experimental group), seton and no treatment (control groups) to compare outcomes with respect to evolution and histopathological analysis of the stulous tract after 30 days of treatment.
Aloe vera represented the highest percentage of stulous closure; it also showed a signi cantly lower stulous path and degree of in ammation compared to the other groups.

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considered an alternative and effective treatment for the different types of wounds mentioned; however, more studies are required regarding its antimicrobial property.respect to mammary ssures and anal ssures, and stulas, it was shown that Aloe vera could be a potential treatment to improve these lesions.Thanks to its low cost and great accessibility by the population, it can be Authorship contributions: The authors participated in the genesis of the idea, project design, data collection and interpretation, analysis of results, and preparation of the manuscript of this research paper.
relation to this, in a preclinical study they treated open skin wounds on the back of 45 rats with AVP, at 25mg or 50mg for 30 days topically, and it was evidenced that, at the transcriptional level, they r e g u l a t e t h e g e n e e x p r e s s i o n o f M a t r i x Metalloproteinase (MMP-3) and Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) during skin repair and this directly helps to regulate the healing activity of Aloe vera gel.Also, they may in uence granulation tissue formation and wound closure by increasing the p r o d u c t i o n o f E C M c o m p o n e n t s , i n c l u d i n g (19) Aloe vera, promotes tissue repair .Its potential molecular mechanisms and role in healing are not very Its healing effect is because aloe vera has a marked effect in the treatment of scar tissue and the prevention of scar formation after injury to the skin.This is because Aloe vera stimulates cell production through the activity of amino acids, which are the basis for new cell formation.Due to the ability of its enzymes, promotes who evaluated the healing effect on second and t h i rd d e g re e b u r n s, a n d a l s o o b s e r ve d l e s s in ammation compared to silver sulfadiazine.
et al. performed their study by applying a seton soaked in glycerin and Aloe vera extract into the stulous tract.Although both studies do not agree that Aloe vera can cause closure of the stulous tract, they do agree that it signi cantly reduces the diameter of the stulous tract, as well as signs of in ammation.

Table 1 .
Pre-clinical and clinical studies evaluating the use of Aloe vera for burn healing.
23 in RatsBurns are lesions in the skin or other organs caused by physical and/or chemical trauma that produce the denaturation of tissue proteins and lead to an alteration Burns THERAPEUTIC EFFICACY

Table 2 .
Preclinical and clinical studies evaluating the use of Aloe vera for surgical wound healing.

Table 3 .
Clinical studies evaluating the use of Aloe vera for breast ssure healing.

Table 4 .
Clinical studies evaluating the use of Aloe vera for the healing of anal ssures.

Table 5 .
Preclinical studies evaluating the use of Aloe vera for anal stula healing.